Synaptic mechanisms underlying noise-induced and age-related hearing loss

描述（申请人提供）：噪声性听力损失（NIHL）和年龄相关性听力损失（AHL）是两种主要的听力障碍，受影响的个体通常表现出处理声音精细时间结构的能力受损。虽然大多数NIHL和AHL的研究都集中在外周缺陷上，但对中枢听觉系统的伴随改变知之甚少。本研究将探讨NIHL和AHL对持有突触终球突触传递的影响及其潜在的细胞机制。这些突触是中枢听觉系统的第一个突触连接，在精细的时间处理中非常重要。初步数据显示，NIHL和AHL损害了小鼠Held终球的突触传递，可能是由于终球末端钙稳态受损。本研究的第一个目的是验证一个假设，即突触前末端钙浓度的升高强调了NIHL后持续活动期间突触释放的异常。突触传递将在正常和NIHL小鼠中进行评估，利用在活性区附近的微域和纳米域修改钙缓冲的操作。钙升高的来源将通过评估突触传递来确定，同时破坏特定途径，包括通过电压门控钙通道的外部钙流入，钙钙调蛋白依赖的钙通道失活，钙诱导钙通过ryanodine受体和IP3受体从内部钙储存中释放。本研究的第二个目的是通过检查突触后丛状细胞的放电特性，探讨NIHL后突触传递变化对功能的影响。这一目的将验证NIHL小鼠中异步释放增加导致突触效能下降和时间精度受损的假设。特别是，本研究还将探索能够在切片中迅速恢复毛状细胞正常放电特性的操作方法。本研究的第三个目的是验证AHL终末球突触传递受损的假说，该假说与NIHL中观察到的钙稳态受损机制相同。与Aims 1和2一样，Aims 3将检测老年AHL小鼠的突触传递和信号通路。本研究的长期目标是确定NIHL和AHL后中枢听觉系统突触改变的共同细胞机制，并在临床前模型中确定可以急性恢复正常突触功能的操作。最终，这些研究可以为NIHL和AHL的未来临床治疗提供方法。

DESCRIPTION (provided by applicant): Noise-induced hearing loss (NIHL) and age-related hearing loss (AHL) are two major hearing impairments, and affected individuals often show compromised ability in processing fine temporal structures of sound. While most studies of NIHL and AHL focus on the peripheral defects, much less is known about accompanying alterations in the central auditory system. This proposal will explore the changes of synaptic transmission and the underlying cellular mechanisms following NIHL and AHL at the endbulb of Held synapses. These synapses are the first synaptic connection of the central auditory system and are well known to be important in fine temporal processing. Preliminary data shows that synaptic transmission at mouse endbulbs of Held is compromised with NIHL and AHL, likely due to impaired calcium homeostasis in the endbulb terminals. The first aim of this proposal will test the hypothesis that elevation of calcium concentration at the presynaptic terminal underlines the aberrant synaptic release during sustained activity following NIHL. Synaptic transmission will be evaluated in both normal and NIHL mice utilizing manipulations that modify calcium buffering in the microdomain and nanodomains near the active zone. The source of the calcium elevation will be identified by assessing synaptic transmission while disrupting specific pathways including external calcium influx via voltage-gated calcium channels, Ca-calmodulin dependent calcium channel inactivation, and calcium induced calcium release from internal calcium stores via ryanodine receptors and IP3 receptors. The second aim of this proposal will explore the functional impact of the changes in synaptic transmission following NIHL by examining the firing properties of postsynaptic bushy cells. This aim will test the hypothesis that increase in asynchronous release in NIHL mice leads to decreased synaptic efficacy and compromised temporal precision. Particularly, the study will also explore manipulations that can acutely restore the normal firing properties of bushy cells in slice. The third aim of this proposal will tst the hypothesis that impaired synaptic transmission at the endbulbs during AHL share the same impaired calcium homeostasis mechanisms as observed in NIHL. As in Aims 1 and 2, Aim 3 will examine the synaptic transmission and test the signaling pathways in aged mice with AHL. The long-term goal of this study is to identify the common cellular mechanisms that underlie synaptic modifications of the central auditory system following NIHL and AHL, and to identify manipulations that can acutely rescue normal synaptic function in a preclinical model. Ultimately, these studies could suggest approaches for future clinical treatments of NIHL and AHL.